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MEDITRANS Résumé de rapport

Project ID: 26668
Financé au titre de: FP6-NMP
Pays: Netherlands

Final Report Summary - MEDITRANS (Targeted delivery of nanomedicine)

The objectives of the MEDITRANS project have been:
- to demonstrate the potential of emerging materials (carbon-based nanoparticles) for use as carrier materials in targeted nanomedicines;
- to develop highly effective nanomedicines based on candidate materials (already used in proof-of-concept drug delivery studies in animals) by virtue of improved targeting and drug release properties;
- to promote the entry of nanomedicines based on established materials into industrial exploitation activities and clinical proof-of-concept studies;
- to develop high-sensitivity imaging probes properly designed for guiding drug delivery processes in vivo;
- to formulate proprietary industrial drug molecules, already established drugs, and DNA- or RNA-based drugs into targeted nanomedicines with well-characterised and optimised physicochemical properties;
- to optimise the targeting efficiency of the nanomedicines under development by in vitro target recognition studies;
- to improve the intracellular targeting of siRNA / pDNA-loaded nanomedicines in cancer and endothelial cells;
- to maximise the drug availability at the target site by means of external physical stimuli that induce drug release from the targeted nanoparticles 'on demand';
- to develop targeted nanomedicines from which release of drug/imaging probe is promoted by physiochemical characteristics of the pathological microenvironment;
- to develop imaging procedures for the monitoring of the various steps in the targeted drug delivery process (nanoparticle targeting and accumulation, drug release, local level of drug and of biomarkers in response to therapy) by means of 'smart' imaging probes;
- to optimise biodistribution, targeting efficiency, and therapeutic activity of the nanomedicines under development in suitable animal models of rheumatoid arthritis, Crohn's disease, multiple sclerosis and cancer;
- to assess the toxicological aspects of selected MEDITRANS nanomedicines;
- to enter selected prototype nanomedicines into an industrial exploitation phase to evaluate their potential to be developed into a marketable product;
- to provide training courses, and access to the Galenos-network, provided for consortium scientists, Small and medium-sized enterprises (SMEs), and key stakeholders;
- to provide effective and efficient dissemination, and demonstration, of the project's results across Europe.

The project was organised into 11 Work packages (WPs), summarised as follows:

WP1: Nanocarrier design aimed at identifying materials suitable for serving as drug delivery devices. Hereto, it on the one hand dealt with the synthesis and characterisation of emerging materials, like fullerenes and nanotubes, as well as, on the other hand, with the evaluation and optimisation of already existing candidate materials, like pDNA- and siRNA-containing polyplexes, polymeric micelles, iron oxide nanoparticles, amino acid-based nanovesicles and stimuli-sensitive liposomes.

WP2: The work performed within this WP over the full duration of the project achieved almost completely all of the planned objectives:
Objective 1) To develop high relaxivity Gd-agents including probes responsive to tissue microenvironmental pH and specific enzymatic activities.
Objective 2) To develop high sensitivity Chemical exchange saturation transfer (CEST) agents including probes able to report about the level of drugs or specific biomarkers within the pathological region.
Objective 3) To develop novel iron oxide particles properly designed for applications in drug delivery processes.
Objective 4) To develop highly sensitive optical imaging probes for monitoring drug delivery processes and therapeutic effects.

WP3 focused on the formulation and physicochemical characterisation of nanocarriers loaded with drugs and imaging agents. In the emerging materials, Carbon nanotubes (CNTs) have been successfully shortened to 100-200 nm and modified with surface functionalities including PEG based chemistries. Budesonide has been loaded onto the CNTs using pyrene / PEG linking chemistry. CNTs have also been loaded with siRNA using two methods. In addition, fullerenes were surface-modified with different functional groups covalently bound with PEG-based stealth polymers. Research on candidate materials included the successful production of a large range of nanoparticles for delivering siRNA and their characterisation with a range of physiochemcial techniques. PLGA based and DOTAP modified nanoparticles, poly(amid amine) dendriplexes, nanoparticles based on DEAPA-PVA-g-PLGA complexes, PEGylated dextran nanogels and PEGylated liposomes have all been prepared.

The objectives of WP4 were to evaluate and optimise the active (by means of targeting ligands or imprints on their surface) or passive targeting efficiency of various nanocarriers for treatment of different pathologies, namely cancer, rheumatoid arthritis, Crohn's disease or multiple sclerosis. The targeting, binding efficiency and ability of the particles to cross the cell barriers, as well as the capacity of the target cells to internalisate the particles, were also to be studied. Whenever necessary, specialised test assays and in vitro models were to be developed.

WP5 offered a standardised test procedure to test the association and dissociation of carriers in buffer, serum and blood, to characterise the intracellular uptake and biological activity of new carriers and to better understand carriers by the use of advanced techniques like Fluorescence correlation spectroscopy (FCS), Single particle tracking (SPT), confocal microscopy, Fluorescence resonance energy transfer (FRET) and Fluorescence recovery after photobleaching (FRAP). Also, the use of PCI to enhance the transfection efficiency is not widely spread. The combination of these techniques and knowledge in one WP makes it possible to study gene delivery complexes in more detail when compared to other labs that do not have access to these advanced microscopy techniques.

The objectives of WP6 have been:
- to maximise availability of nanoparticle-bound drugs to target cells by using external stimuli to induce drug release from the targeted nanocarriers 'on demand';
- to optimise the release of the drug / imaging probe payload from the nanocarrier in response to physicochemical characteristics of the biological microenvironment;
- to develop MRI procedures for the quantitation of in situ drug availability and delivery by means of 'smart' imaging probes.

WP7 evaluated and explored the preparation, characterisation and application of several nano-particle systems for the diagnostics and treatment of chronic inflammation-related diseases like RA and CD. At the start of MEDITRANS, the partners in this WP already had considerable expertise in this area and there were extensive links with several other WPs. While the proposed nanomedicines containing corticosteroids had already been preclinically evaluated in RA models, the in vivo imaging of drug treatment effects and drug delivery in cvcvcv relevant mouse models was new. The application of these formulations to treat CD is also a major innovation. The other therapeutic approaches that were proposed for preclinical evaluation were also so far unexplored.

The objectives of WP8 at the beginning of the MEDITRANS project were:
1. to study pharmacokinetics, tissue distribution, targeting efficiency and therapeutic efficacy of the developed targeted nanomedicines in suitable animal models of MS. (Task 8.1 - Passive targeting approach; Task 8.2 active targeting approach);
2. to design and optimise a carrier for imaging-guided drug release and delivery in the Central nervous system (CNS) (Task 8.3 - MRI guided drug delivery);
3. to evaluate, in vivo, the therapeutic efficacy of MMP-inhibitors, through imaging-guided targeted and triggered delivery, in CNS lesions induced by MS-like pathology (Task 8.3 - MRI guided drug delivery).

Final decision from RBM (renamed MSSA after major company reorganisation) to withdraw from the MEDITRANS consortium (last quarter of 2009) has made it mandatory to revise the objectives, workplan and deliverables of WP8.

The objectives of WP9 at the beginning of the MEDITRANS project were:
- to study pharmacokinetics, tissue distribution, targeting efficiency, and therapeutic efficacy of the developed targeted nanomedicines in suitable animal models of cancer;
- therapeutic evaluation of MRI-guided drug delivery (triggered release) in animal models of cancer.

The work performed in WP10 aimed at studying the potential adverse effects of the selected nanomedicines, prior to clinical studies. The work plan was based on safety pharmacology tests which included pharmacokinetic, biodistribution, and toxicology studies. Four nanomedicines were selected among the various candidates investigated in MEDITRANS: two nanomedicines for the treatment of cancer (i.e. liposomal dexamethasone and polymeric micelles) and two nanomedicines for imaging-guided drug delivery (i.e. liposomal gadolinium and ultrasmall superparamagnetic iron-oxide (P904 USPIO)). The collected data are important prior to human trials and identification of clinical monitoring parameters.

As a result of the withdrawal of BSP, Organon and RBM, from WP10 and WP11, there was a need to restructure these WPs in the third year. The activities described below commenced as soon as possible in the fourth year. The following nanomedicines have been selected for further study in WP10 and WP11:
1) liposomal dexamethasone for treatment of cancer (UU);
2) polymeric micelles for treatment of cancer (UU);
3) liposomal gadolinium for imaging guided drug delivery (BRACCO);
4) ultrasmall superparamagnetic iron-oxide (USPIO) nanoparticles for imaging guided drug delivery (Guerbet).
To bring nanomedicine-based products to the patient, many activities are necessary and include aspects like upscaling, validated analysis, packaging issues and the production of nanomedicines as sterile products. In WP11, several essential development steps have been successfully taken.

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